U.S. Pat. No. 3,722,504 describes a screen for testing pharmaceutical compounds based at least partly on their ability to increase the negative surface charge of the vascular system. U.S. Pat. No. 3,722,504, by way of example, discloses a pharmaceutical compound which prevents thrombosis by modifying the intimal surface charge of the vascular system.
Para amino benzoic acid increases the net negative surface charge of blood vessels and blood cells. It produces marked increases in the current induced occlusion time in rat mesentary vessels (see U.S. Pat. No. 3,956,504). It produces no measurable effect on blood coagulation studies. It has a limited effect on blood vessel wall pores as shown by electro-osmotic studies.
Para amino benzoic acid, further, has good antithrombotic characteristics but tends to have relative little anti-coagulant activity as shown by its lack of effect on the coagulation studies including partial thromboplastin time, thrombin time and recalcification time. It is therefore a very useful antithrombotic drug.
Para amino benzoic acid has various very significant properties as a drug:
1. It is inexpensive; PA1 2. It is known to be non-toxic in humans; PA1 3. It can be used for long periods of time without significant incidence of pathological manifestations. PA1 4. The material can be taken orally in large dosages without significant toxicity. PA1 1. It is a co-enzyme in the Kreb's cycle. PA1 2. It is a reducing agent and electron donor in 11 known biological systems.
In man, dosages have been administered, for example, as high as 12 to 24 grams a day without significant side effects. It has furthermore been used for a large number of diseases in man including the therapy of Ricketsial diseases before the development of anti-biotics, for tuberculosis in very large dosage and in the treatment of certain protozoan diseases and other infestation. It has long been thought to be a mild anti-inflammatory agent.
In humans with arteriosclerotic peripheral vascular disease, para amino benzoic acid has been shown to increase blood flow in ischemic limbs as measured by Barcroft plethysmographic studies and Doppler blood flow measurements. Studies which were carried out in approximately fifty patients resulted in an approximate doubling of blood flows in patients in which para amino benzoic acid salt was effective. U.S. Pat. No. 3,956,504 has been issued on the effect of para amino benzoic acid on blood flow in man.
The long term effects of vitamin C on scurvy in man is a primary event of historical interest in medicine. The effects of vitamin C to prevent scurvy are extraordinarily well documented throughout the world. Man, deprived of vitamin C for periods longer than approximately sixty days, starts to display evidence of capillary fragility and bleeding into all tissues and organs. Vitamic C has the following characteristics:
L-ascorbic acid or vitamin C has a variety of biological functions some of which are not completely understood (Zitent et al 1964). Large doses of L-ascorbic acid appear to have value in prevention and symptom reduction in the common cold and other viral diseases (Linus Pauling 1974). Recent experimental evidence indicates that L-ascorbic acid is effective in reducing serum cholesterol levels. C. Spittle (The Lancet, July 28, 1973; pp. 199-201 and Dec. 11, 1971; pp. 1280-1281) suggested that dosages of 1 to 2 grams of vitamin C per day can be beneficial in the prevention of deep vein thrombosis as well as in reducing the incidence of atherosclerotic complications in man. Recent research indicates that ascorbic acid may reduce the incidence of myocardial infarction (Knox, E. G., The Lancet, pp. 1465, June 30, 1973). L-ascorbic acid, further, appears to offset the thrombogenic effects of oral contraceptives as demonstrated by prolongation of occlusion times in the mesenteric vessels.
Good results were obtained in a pilot study using seven volunteer subjects to determine the effects of ascorbic acid on (1) plasma coagulation characteristics (2) serum cholesterol levels (3) platelet aggregability and (4) surface charge characteristics of red cells and platelets. Vitamin C in these subjects was shown to decrease platelet aggregability and increase the electro-phoretic mobility of all the tested cells.
There has been little evidence to indicate that vitamin C effects measured blood coagulability as demonstrated by partial thromboplastin time, thrombin times and thrombin recalcification times.
Spittle et al have tested vitamin C in a randomized group of patients with thrombophlebitis. The protective effect of vitamin C against thrombosis has been shown by a randomized double-blind trial using patients who were shown to be prone to deep-venous thrombosis. In a total of fifty-three patients, it was observed that the incidence of deep venous thrombosis was 33% in patients dosed with L-ascorbic acid compared to 60% in the placebo group (Spittle, C. R., The Lancet, pp. 199, July 28, 1973). The dose given was 1 gram per day. This correlation between the intake of vitamin C and reduction in the number of thrombotic episodes has been confirmed by other sources. In burn patients, where it is customary to use large doses of vitamin C to speed healing, there has been an apparent demand for treatment of deep-vein thrombosis. This information is based on the experience of one hospital over a five and one-half year period during which time 159 patients over forty years of age were treated with large doses of vitamin C (Spittle, C. R., "The Action of Vitamin C on Blood Vessels," Amer. Heart J. 88: 387, 1974).
A combination of para amino benzoic acid and vitamin C has been shown, for example, in Runti, I1 Farmaco, Ed. Sci., Vol. X, 1955, pp. 424-431.